Therapeutic gas for the treatment of mitochondrial disorders

ABSTRACT

The use of gaseous oxygen for the production of a therapeutic gas for inhalation by a patient who has been identified as a person with a mitochondrial disorder or a coenzyme Q10 deficiency, for the treatment of mitochondrial disorders or Q10 deficiencies is disclosed. For the first time a non-invasive method is disclosed, upon what the body&#39;s own level of Q10 can be raised significantly without further interventions.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 13/504,821, inventor Bernd-Michael Loeffler, filed Apr. 27,2012, which was the National Stage of International Application No.PCT/EP2010/066288, filed Oct. 27, 2010, the disclosures of which areincorporated herein by reference.

The invention relates to the use of gaseous oxygen for the production ofa therapeutic gas for inhalation by patients.

It is known that inhalation of oxygen-deficient air is used for theacclimatization of human bodies to high altitudes, particularly withregard to journeys of people to high mountain areas like the Himalayasor Tibet. But also athletes make use of this method which is known asaltitude training to advance their physical ability in standardconditions.

The Interval-Hypoxia-Training (IHT) is a method of acclimatization toaltitudes. In this process people inhale oxygen-deficient air (14-9% O₂)through a mask what initiates acclimatization activities in the body.Cyclical changes between oxygen-deficient air and ambient air make thisaltitude training highly efficient.

The Chronic fatigue syndrome (CFS) is a chronic disease which oftencauses invalidity. It is characterized by a paralyzing mental andcorporal exhaustion/exhaustibility as well as by a specific combinationof further symptoms.

Beside chronic exhaustion, symptoms are, among others, headache, sorethroat, joint and muscle pain, difficulties in concentration,disturbance of memory, less restful sleep, sensibility of lymph nodes aswell as lasting debasement of fitness condition after exertion.

It is supposed, that CFS might be a result of mitochondrial disorders oroxidative stress, beside other unspecific diseases.

Oxidative stress is a metabolic status in which an amount of reactiveoxygen species (ROS) is build or available, that is beyond thephysiological levels. Those reactive oxygen species arise in line withmetabolic processes of the mitochondrial electron transport chain andcytochrome-P₅₀-oxidases. These oxygen species are the peroxide anionradical O₂ ⁻, hydrogen peroxide (H₂O₂) and hydroxyl radical OH (SchmidtR. F., e.a.: Physiologie des Menschen, Springer, 2007, p. 957 ff.).

Normal organism cells keep their ability to absorb reducing or oxidisingsubstances alive by storing reserves of reducing or oxidisingsubstances. An imbalance between these pools, which overcharges thenormal function of repair and detoxication of cells and therefore causesa damage of all cellular and extracellular macromolecules, is calledoxidative stress (David Heber, George L. Blackburn, Vay Liang W. Go,John Milner (Ed.): Nutritional Oncology. Academic Press, 2006. p. 314).

A possible treatment of this disease consists in application of Q10(ubiquinone). Ubiquinone (also named UQ, coenzyme Q, CoQ, Q or coenzymeQ₁₀) is a quinone derivative with a lipophilic isoprenoid side chain,structurally refated to vitamin K and vitamin E. The reduced phenolicform is called ubihydrochinone or ubiquinol (QH₂). Q10, coenzyme Q, isan essential vector of electrons and protons between complex I andcomplex II, respectively, and complex III of the respiratory chain.

Some deficiency symptoms of Q10 also appearing may have differentreasons.

The current most known situation of reduction of Q10 by medication isadministration of statines to decrease the cholesterol level and LDL.The synthesis of mevalonic acid gets blocked, which is a collectivejunction for the production of cholesterol or Q10. Consequences for thepatients are partly extensive: muscle pain, restricted walking distancecomparable to intermittent claudication, general faintness, tiredness.They are generally not worked therapeutically with.

There is a raising amount of different indications known for loweredQ10, and for giving significant amendments by substitution of Q10 to“therapeutic” Q10 serum level. These are, among others, cardiacinsufficiency, migraine, tinnitus. Further there are correlationsbetween lower Q10 levels and cancer, Q10 and immune system anddepressions.

The Q10 level is different in various organs and the highest levels arefound in myocardial muscle cells. Q10 declines by raising age. Generallyit is assumed that Q10 is no vitamin because the body is able to produceenough Q10 by self synthesis. But this is apparently in many situationsnot the case (e.g. chronic diseases), but also in “as healthy knownprobands” one can find extensive lowered levels of Q10, without anapparent external cause. The standard value of Q10 is 0.8-1.15 mg/l, thepreventive medical rated range is >1.4 mg/l, the therapeutic areais >2.5 mg/l.

The object of the invention is providing means to medicate mitochondrialdisorders and to elevate the concentration of Q10 in plasma of patients.

The object is solved by use of gaseous oxygen for the production of atherapeutic gas for inhalation according to the main claim.

Thus the object is solved by use of gaseous oxygen for the production ofa therapeutic gas for inhalation by a patient who has been identified asa person with a mitochondrial disorder or a Q10 deficiency, for thetreatment of mitochondrial disorders or the Q10 deficiencies.

According to the invention the use is preferred, in which the inhalationof the therapeutic gas is performed in at least two sections.

Especially preferred is the use according to the present inventionwherein the concentration of the oxygen in the therapeutic gas has adifferent amount in the respective sections.

Especially preferred is the use according to the present inventionwherein the concentration of the oxygen in the therapeutic gas is fromabout 15 Vol-% to about 9 Vol-%.

Especially preferred is the use according to the present inventionwherein the concentration of the oxygen in the therapeutic gas is fromabout 30 Vol-% to about 55 Vol-%.

According to the present invention the use is especially preferredwherein the respective sections of inhalation last from 1 minute up to60 minutes.

Furthermore according to the invention the use is especially preferredwherein the total time of inhalation lasts from 10 minutes up to 5hours.

Also preferred is the use wherein the oxygen partial pressure in thepatient is detected during inhalation.

Exceptionally preferred is the use wherein the mitochondrial disorder orthe Q10 deficiency to be treated is associated with: cardiacinsufficiency, arrhythmias, cardiac arrest, tinnitus, acute hearingloss, senile ablepsia, age-related macular degeneration, parodontitis,gingivitis, cancer, solid tumour, Attention Deficit/hyperactivityDisorder (ADHD), autism, Attention Deficit Disorder (ADD), parkinsonism,dementia, Alzheimer's disease, olfactory disorders, migraine,neuropathic pain, pruritis, asthma, chronic obstructive pulmonarydisease (COPD), apnoea, dialysis, apheresis, incontinence,neurodermatitis, psoriasis, wound healing, type 2 diabetes, overweight,obesity, metabolic syndrome, multiple sclerosis, allergy.

An especially preferred use according to the present invention is toelevate or increase the plasma levels of coenzyme Q10 in a patient.

In other words, the main object of the invention is to provide a methodfor the treatment of a patient having mitochondrial disorders orcoenzyme Q10 deficiencies, and that the method consists of administeringa therapeutic gas to the patient, and that the therapeutic gas containsdifferent levels of oxygen, forming either a hypoxic or a hyperoxictherapeutic gas that is administered to the patient in a regime, inwhich the level is changed from one section to the other from hypoxic tohyperoxic and back to hypoxic and so on.

The “Intermittent Hypoxia-Hyperoxia-Therapy” (IHHT), as it is called bythe inventor, is a new therapy method that can be used for a wide rangeof diseases that are correlated with mitochondrial disorders and/orcoenzyme Q10 deficiencies.

In the art there are methods known as intermittent hypoxia(“Intermittent Hypoxia: From Molecular Mechanism To ClinicalApplications”; Lei Xi and Tatiana V Serebrovskaja (Eds.) 2009 NovaScience Publishers Inc. New York). The main difference to known methods(Diving: Normoxia with Hypoxia and simultaneous Hypercapnia (elevationof CO₂ levels in blood); von Ardenne method: Normoxia Hyperoxia, methodwith ozone (Normoxia-Ozone); so-called Hypobaric Hypoxia: Hypoxia withsimultaneous pressure reduction of the air to breath) is that anormobaric hypoxia (15-9% O₂) hyperoxia (30-55% O₂) method is used.

Furthermore, Hypoxia is described in the art as a dangerous principle asthe method is compared to obstructive-sleep-apnoea (OSA). In contrast,OSA differs from IHHT, in that the intervals and the duration of Hypoxiasections are regulated.

Surprisingly it was found, that the concentration of Q10 raises in theblood of the patients, if cycles of inhalation of hypoxygenic andhyperoxygenic gases follow each other. Thereby it is advantageous tocarry out these cycles several times following successively one afterthe other and thereby forming a session and repeating the completesession in predefined intervals.

For the first time a non-invasive method is disclosed, whereby thebody's own level of Q10 can be raised significantly without furtherinterventions or medications. Up to now it was only possible to elevatethe plasma levels by administering Q10 orally or parenterally to apatient in need of such a medication.

By using cycles of inhalation of hypoxygenic and hyperoxygenic gases itis possible to elevate the plasma levels of Q10 in a patient up to thetherapeutic range of 2.5 mg/l without any problem.

As the plasma level of coenzyme Q10 is believed to be highly relatedwith many diseases of the heart, brain, eyes, lungs, bladder, kidneys,skin, nervous system, sense of hearing, and also with pain and cancer,it is a great advantage to elevate the plasma level in a patient withoutexternal administration of the coenzyme Q10. The body's-own productionof coenzyme Q10 is stimulated by the inhalation of hypoxygenic andhyperoxygenic gases.

Further it was found that by a capable oral therapy with so-called“mitogen substances” (e.g. acetyl salicylic acid, vitamins, alphaliponic acid, minerals, Zn, Mn, etc.) the effect of the oral therapywith Q10 can be clearly amplified. Consequently, the same applies to themethod of the invention so that co-medication with mitogen substancesmay be carried out.

It is apparent from the description of the invention that the levels ofoxygen in the respective hypoxygenic and hyperoxygenic gases may beadjusted and easily optimized for a certain disease. It is possible fora skilled artesian to optimize those levels using the teaching of thepresent invention without deviating from the scope of the claims givenherein.

The following examples explain the invention in greater detail.

EXAMPLE 1

18 test persons were chosen and concluded the test. The test persons getrandomized after an initial check-up into a control group (N=8) and atreatment group (N=10).

Within three weeks all of the test persons graduated ten inhalationproceedings of 36 minutes in each case. The persons belonging to thecontrol group respired ambient air through an air supply tube of therespiration apparatus (tube not connected), the treatment group respiredfor 6 minutes 12 Vol.-% O₂, afterwards for 3 minutes 44 Vol.-% O₂. Thiscycle was repeated three times, so that altogether four cycles werecompleted, forming an inhalation session of 36 minutes. The lowest valuefor pCO₂ was defined to 80%.

After completion of the ten treatment units all test persons wereexamined again.

The inhalation was arranged by using an ordinary respiration apparatus.Analogous apparatus are known from the IHT. Those apparatuses wereaccordingly modified, so that next to hypoxygenic gases alsohyperoxygenic gases with an oxygen content of 30-55 Vol-% can beventilated.

Monitoring of oxygen partial pressure of the test persons blood wasperformed using a commercially available equipment as for example givenin DE 92 08 590 U1.

The results of the collected physiological parameters of the testpersons are presented in Table 1. The values of NPE (3-nitro phenylacetic acid) and citrulline have been measured in the urine, the valuesfor MMS (methyl malonic acid), Q10 (coenzyme Qn), and Mito Act(mitochondrial activity) in the blood of the test persons.

TABLE 1 Param- Control group Treatment group eter Mean SD pTT Mean SDpTT uTT NPE before 7.52 11.70 0.37 10.09 15.17 0.244 after 29.05 71.1733.11 46.57 Citrulline before 5.89 3.39 0.94 8.29 9.59 0.845 after 5.386.05 7.59 4.46 MMS before 0.94 0.46 0.25 1.02 1.37 0.325 after 1.05 0.330.53 0.33 Q10 before 0.78 0.26 0.02 0.96 0.31 0.000 0.23 after 0.91 0.311.37 0.35 0.02 Mito Act before 86.28 12.41 0.16 84.74 6.59 0.004 0.77after 94.03 5.14 94.57 4.31 0.84 Statistical analysis: Mean: Mean valueSD: Standard deviation. pTT: paired T-Test, 2-tailed for unequallyvariance of the groups within the groups for indicated valuesbefore/after treatment. uTT: unpaired T-Test between treatment group andcontrol group.

EXAMPLE 2

A patient showing symptomatic disorders caused by chronic borreliosiswas treated 1 minute with 13 Vol-% hypoxia and 9 minutes with 38 Vol-%hyperoxia in 6 cycles forming a session of one hour duration.

A significant improvement of the skin structure and the aspect of theskin was achieved after 10 sessions. The improvement remained for about3 months.

1. A method for the treatment of mitochondrial disorders or coenzyme Q10deficiencies, the method comprising: a) identifying a person with amitochondrial disorder or a coenzyme Q10 deficiency; and b)administering to the person via inhalation a therapeutic gas comprisinggaseous oxygen in the form of an intermittent hypoxia-hyperoxia therapy,wherein sessions of inhalation of hypoxygenic and hyperoxygenic gasesalternate and wherein the concentration of oxygen in the therapeutic gasis from about 15 Vol-% to about 9 Vol-% for a hypoxia session; whereinthe inhalation of the therapeutic gas results in an increase of coenzymeQ10 to a therapeutic range of 2.5 mg/l in plasma of the person. 2.(canceled)
 3. (canceled)
 4. (canceled)
 5. The method according to claim1, wherein the concentration of the oxygen in the therapeutic gas isfrom about 30 Vol-% to about 55 Vol-% for a hyperoxia session.
 6. Themethod according to claim 1, wherein the respective sessions ofinhalation last from 1 minute up to 60 minutes.
 7. The method accordingto claim 1, wherein the total time of inhalation lasts from 10 minutesup to 5 hours.
 8. The method according to claim 1, wherein an oxygenpartial pressure in the person is measured during inhalation.
 9. Themethod according to claim 1, wherein the mitochondrial disorder or theQ10 deficiency to be treated is associated with a member selected fromthe group consisting of cardiac insufficiency, arrhythmias, cardiacarrest, tinnitus, acute hearing loss, senile ablepsia, age-relatedmacular degeneration, parodontitis, gingivitis, cancer, solid tumour,attention deficit/hyperactivity disorder (ADHD), autism, attentiondeficit disorder (ADD), parkinsonism, dementia, Alzheimer's disease,olfactory disorders, migraine, neuropathic pain, pruritis, asthma,chronic obstructive pulmonary disease (COPD), apnoea, dialysis,apheresis, incontinence, neurodermatitis, psoriasis, wound healing, type2 diabetes, overweight, obesity, metabolic syndrome, multiple sclerosis,and allergy.
 10. (canceled)
 11. The method as claimed in claim 1 whereininhalation of the gas is performed in at least two time sessions, one ofthe time sessions being a hyperoxia session in which the concentrationof the oxygen in the therapeutic gas is from about 30 Vol-% to about 55Vol-%.
 12. A method for the treatment of coenzyme Q10 deficiencies, themethod comprising: a) identifying a person with a coenzyme Q10deficiency; and b) administering to the person via inhalation atherapeutic gas comprising gaseous oxygen in the form of an intermittenthypoxia-hyperoxia therapy, wherein the therapeutic gas has an oxygenconcentration from about 15 Vol-% to about 9 Vol-% for a hypoxiainterval; wherein the inhalation of the therapeutic gas results in anincrease of coenzyme Q10 to a therapeutic range of 2.5 mg/l in plasma ofthe person.
 13. The method according to claim 1, wherein inhalation ofthe gas is performed in at least two time sessions, one of the timesessions being a hyperoxia session in which the concentration of theoxygen in the therapeutic gas is from about 38 Vol-% to about 55 Vol-%.14. The method according to claim 1, wherein inhalation of the gas isperformed in at least two time sessions, one of the time sessions beinga hyperoxia session in which the concentration of the oxygen in thetherapeutic gas is from about 44 Vol-% to about 55 Vol-%.
 15. A methodfor the treatment of mitochondrial disorders or coenzyme Q10deficiencies, the method comprising: a) identifying a person with amitochondrial disorder or a coenzyme Q10 deficiency; and b)administering to the person via inhalation a therapeutic gas comprisinggaseous oxygen in the form of an intermittent hypoxia-hyperoxia therapy,the intermittent hypoxia-hyperoxia therapy comprising a hypoxygenicsession and a hyperoxygenic session, wherein one of the hypoxygenicsession and the hyperoxygenic session follows the other of thehypoxygenic session and the hyperoxygenic session, and wherein theconcentration of oxygen in the therapeutic gas is from about 15 Vol-% toabout 9 Vol-% for the hypoxia session; wherein the inhalation of thetherapeutic gas results in an increase of coenzyme Q10 to a therapeuticrange of 2.5 mg/l in plasma of the person.